title: Importin-mediated retrograde transport of CREB2 from distal processes to the nucleus in neurons.
abstract: Signals received at distal synapses of neurons must be conveyed to the nucleus to initiate the changes in transcription that underlie long-lasting synaptic plasticity. The presence of importin nuclear transporters and of select transcription factors at synapses raises the possibility that importins directly transport transcription factors from synapse to nucleus to modulate gene expression. Here, we show that cyclic AMP response element binding protein 2 (CREB2)/activating transcription factor 4 (ATF4), a transcriptional repressor that modulates long-term synaptic plasticity and memory, localizes to distal dendrites of rodent hippocampal neurons and neurites of Aplysia sensory neurons (SNs) and binds to specific importin alpha isoforms. Binding of CREB2 to importin alpha is required for its transport from distal dendrites to the soma and for its translocation into the nucleus. CREB2 accumulates in the nucleus during long-term depression (LTD) but not long-term potentiation of rodent hippocampal synapses, and during LTD but not long-term facilitation (LTF) of Aplysia sensory-motor synapses. Time-lapse microscopy of CREB2 tagged with a photoconvertible fluorescent protein further reveals retrograde transport of CREB2 from distal neurites to the nucleus of Aplysia SN during phenylalanine-methionine-arginine-phenylalanine-amide (FMRFamide)-induced LTD. Together, our findings indicate that CREB2 is a novel cargo of importin alpha that translocates from distal synaptic sites to the nucleus after stimuli that induce LTD of neuronal synapses.
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Brain Research Institute, University of California, BSRB 390B, 615 Charles E. Young Drive S, Los Angeles, CA 90095-1737, USA.
authors.forename: Kwok-On
authors.initials: KO
authors.lastname: Lai
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhao
authors.forename: Toh Hean
authors.initials: TH
authors.lastname: Ch'ng
authors.forename: Kelsey C
authors.initials: KC
authors.lastname: Martin
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D018929:Cell Culture Techniques; D002467:Cell Nucleus / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019835:FMRFamide / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017729:Presynaptic Terminals; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism*; D014162:Transfection; D028901:alpha Karyopherins / Q000378:metabolism*
chemical_list: C097204:ApCREB2 protein, Aplysia californica; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D028901:alpha Karyopherins; D019835:FMRFamide